Citation:

Demarini, D. Identification of Human Germ-Cell Mutagens. Brazilian Environmental Mutagen Society, Bento Goncalves, Rio Grande Do Sul, BRAZIL, June 03 - 06, 2019.

Impact/Purpose:

Although no agents have been evaluated as human germ-cell mutagens by any national or international organization, there is emerging evidence that ionizing radiation, tobacco smoking, and air pollution may be human germ-cell mutagens. Definitive evidence must await next-generation whole genomic DNA sequencing of mother-father-child trios in which the father (but not the mother) had chronic exposure to one of the three agents noted above--and the finding that the child has more mutations and different ones than are present in either parent. Regulatory agencies will need to be prepared for such an outcome in the coming decade, and this presentation outlines the emerging evidence that suggests that the three agents listed above might be human germ-cell mutagens.

Description:

The existence of agents that can induce germ-cell mutations in experimental systems has been recognized since 1927 with the discovery of the ability of X-rays to induce such mutations in Drosophila. Various rodent-based germ-cell mutation assays have been developed, and ~45 germ-cell mutagens have been clearly identified in these rodent assays. Overall, >160 agents have some evidence that they can induce germ-cell mutations in rodents. However, no agent has been declared a germ-cell mutagen in humans. Nonetheless, evidence is emerging that ionizing radiation, air pollution, and tobacco smoke may be human germ-cell mutagens. The International Agency for Research on Cancer (IARC) is part of the World Health Organization that evaluates agents for their ability to be human carcinogens. The criteria used by IARC could be modified to evaluate an agent for its ability to be a human germ-cell mutagen. Sufficient evidence in animals would require that the agent induce germ-cell mutations in at least 2 species or that there be 2 independent positive studies in one species. In addition, in vitro, rodent, and human biomarker data would be necessary to provide sufficient mechanistic evidence in humans. Epidemiological evidence and exposure assessment would also be considered in the evaluation. Applying such criteria, the current literature indicates that there would be sufficient evidence to evaluate ionizing radiation, tobacco smoking, and air pollution as Group 1 (known) human germ-cell mutagens. Definitive molecular epidemiological evidence in the form of next-generation, genomic DNA sequence analysis, will likely provide the definitive evidence to support such evaluations. [Abstract does not necessarily reflect the views or policies of the U.S. EPA.]

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